Dearomative Photocatalytic Hydroalkylation and Lipophilic Prodrugs Öffentlichkeit

Abstract

Dearomatization has become a powerful technique to create dimensional complexity from inexpensive, abundant aromatic precursors. Here, we employed intramolecular cyclization of alkyl radicals for dearomatization of benzylacetamides to form spirocyclic lactams. A strongly reducing organic photocatalyst with a stoichiometric amine reductant was used to afford the 1,4-cyclohexadiene moieties by a reductive radical polar crossover mechanism. The reaction was optimized to favor the dearomatized product over hydrodehalogenation and dimer byproducts. The regioselective method proceeds efficiently on a range of substituted benzylacetamides. Additionally, the dearomatized products can be functionalized to afford a variety of scaffolds, including the commonly prescribed anticonvulsant drug, Gabapentin.

Nucleoside analogues have emerged as effective therapeutics by interfering with endogenous nucleosides to prevent viral replication and tumor proliferation. Here we develop nucleoside prodrug analogues to increase selectivity, and decrease degradation and toxicity. A Tenofovir prodrug was developed with a glycerol backbone with oxygen linkers connecting TFV to inhibit reverse transcriptase, a lipophilic chain to improve cell permeability, and varying lipophilic groups to increase lipoprotein association and direct transport to systemic circulation. The 5-fluorouracil prodrug analogue incorporates the active metabolite FdUMP prevent 5-FU degradation, steric bulk to limit kinase activity, and a metabolically stable chain to decrease premature drug release.

Table of Contents

Dearomatization of Unactivated Arenes via Photocatalytic Hydroalkylation………1

Introduction……………………………………………………………………………,,,,,…..1

Results and Discussion……………………………………………………………………....7

Conclusion and Future Work……………………………………………………………....16

Lipophilic Tenofovir Prodrugs…………………………………………………………………18

Introduction………………………………………………………………………......………18

Results and Discussion…………………………………………………………….....……..26

Conclusion and Future Work…………………………………………………………....….31

Fluorodeoxyuridine Monophosphate Prodrugs………………………………...…………32

Introduction…………………………………………………………………………......…....32

Results and Discussion………………………………….…………………………....……..39

Conclusion and Future Work…………………………………………………………....….41

References………………………………………………………………...…………………..…..42

Experimental ……………………………………………………………..………………...…….48

About this Master's Thesis

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Chemistry
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Chemistry, Organic
Stichwort	Photochemistry Dearomatization Prodrugs
Committee Chair / Thesis Advisor	Liotta, Dennis, Emory University
Committee Members	Wuest, William, Emory University Blakey, Simon, Emory University

Zuletzt geändert

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	Dearomative Photocatalytic Hydroalkylation and Lipophilic Prodrugs ()	2021-12-09 13:22:42 -0500	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions